Guide to Biobanks in Sweden –Access to Samples for Research and Clinical trials

1 Foreword The information in this guide is aimed at better characterisation of various cancer tumours, research that requires access to samples – and how these characteristics affect prognosis research initiated by a medical technology or and need for treatment. This has led to improved pharmaceutical company, a county council/ diagnostics and new pharmaceutical drugs and region or a university. treatments as well as personalized therapies. An Sweden has good conditions and a good association between certain HPV viruses and cancer climate for research and clinical trials including was found by comparing stored samples collected in human biological samples (hereinafter referred to gynaecological healthcare for cervical cancer. This as samples). There are national quality registers, insight led to changes in the cervical cancer screening national health data registers and biobanks with program and the development of the HPV vaccine, millions of samples that can be linked for research, which today is included in the child vaccination upon approval from an Ethics Review Board. program. Samples are important for the development of Within healthcare and universities, there are diagnostic markers, new pharmaceutical drugs and comprehensive and well-defined sample collections personalized treatments for a variety of diseases, for care and research, scientific and clinic such as rheumatic disease, inflammatory disease, competence, established service functions for diabetes, cardiovascular disease, psychiatric disease administrative, regulatory and operational support in and many more. By combining collected samples planning and implementation of different types of with information on the patient, care in Sweden has studies, as well as joint enforcement of the Swedish been improved. In addition to the immediate benefit Biobanks in Medical Care Act. An important for patient care and treatment, there is awareness that prerequisite for Sweden’s successful biobanking is the access to samples provides opportunities for research positive attitude to research on part of the public and generating new knowledge of causes of diseases, patients. diagnoses, diagnosis classifications, improved A collaboration has been established between county treatments, new pharmaceutical drugs and vaccines. councils/regions, medical universities and industry In cancer research, stored tissue samples have organisations regarding a national infrastructure for enabled cancer care to develop significantly, through biobanks to facilitate research and development.

ABOUT THIS GUIDE This guide describes biobanks in Sweden and how samples can be used in research and clinical trials. The document provides guidance on what researchers and companies should do to get access to existing samples in Swedish biobanks, as well as requirements for collecting new samples from persons in Sweden. It also provides guidelines for researchers and companies regarding biobank services available for the collection of new samples and the release of samples. The purpose of this guide is to contribute to making shared resources available and ensure that support is used optimally and with respect for the integrity of patients and donors.

2 Content 1. BIOBANK SWEDEN 4 2. BIOBANKS IN SWEDEN 6 3. EXISTING SAMPLE COLLECTIONS IN SWEDISH BIOBANKS 8 4. COLLECTING NEW SAMPLES 10 5. NATIONAL REGISTERS AND QUALITY REGISTERS 11 6. RULES AND REGULATIONS FOR BIOBANKS 13 7. BIOBANK APPLICATIONS 17 8. OWNERSHIP AND PUBLICATION 21 9. WHAT CAN I DO TO FACILITATE THE APPLICATION PROCESS? 22 10. ADVICE AND PRACTICAL SUPPORT 22 11. AGREEMENTS AND INSTRUCTIONS 23 12. PLANNING 24 APPENDIX 1. VOCABULARY 25 APPENDIX 2. ROLES AND SERVICES 26 APPENDIX 3. DEFINITIONS OF ENTITIES RESPONSIBLE FOR A PROJECT 27

3 ...collaboration aims at producing science based on biobank samples for the benefit of public health and the individual ”patient.”

1. Biobank Sweden In the spring of 2017 a new agreement was reached In May 2017, the industry organisations between county councils/regions with university Läkemedelsindustriföreningen (LIF), Swedish hospitals and universities with a medical faculty, Medtech, Swedish Labtech and SwedenBIO also for enhanced collaboration to support biobank joined the main agreement with the purpose of infrastructure for healthcare, academia and industry increasing the competitiveness of Swedish medical (medical/technical/pharmaceutical). To implement research and development, and with the aim to the agreement, the association “Biobank Sweden” promote the development of healthcare. A good was established (former National Biobank Council collaboration between industry, healthcare and and BBMRI.se). universities promotes coordination of resources The agreement originates from the county made available through the existing collaboration councils/regions responsibility for healthcare, between biobanks, on both a national and local level, and the universities responsibility for research as well as within the healthcare regions. and education, as well as the universities need Biobank Sweden consists of a National Steering to collaborate with healthcare in order to fulfil Committee, with representatives appointed by their responsibilities. The goal of the extended the county councils/regions and universities with collaboration is to build a joint, improved and a medical faculty and with representation from sustainable national biobank infrastructure for industry organisations, a strategic preparatory healthcare, academia and industry with the best group, two working committees for regulatory conditions for both national and international and operative biobank service and a national collaboration. The enhanced collaboration aims network with the county councils’/regions’ biobank at producing science based on biobank samples coordinators (Swedish: “Biobankssamordnare”). In for the benefit of public health and the individual Biobank Sweden, which is supported by the Swedish patient. Biobank Sweden also aims to facilitate the Association of Local Authorities and Regions, enforcement of the Swedish Biobanks in Medical representatives from patient organisations are also Care Act. included.

4 5 2. Biobanks in Sweden In Sweden, there are 7 universities with a medical companies as well as biobanks at some authorities faculty and 21 county councils/regions, each being (approximately 200 in total). Several of the biobanks their own principal. Together, they have nearly that are not included in the healthcare sector are 250 biobanks containing over 150 million samples so-called e-biobanks (or virtual biobanks), implying and approximately 3-4 million samples are added they contain only sample data and no samples. each year. The most extensive biobanks and largest The e-biobanks are established with the purpose quantity of samples are stored in the county of following the requirements of the Biobanks in councils’/regions’ 200 biobanks (estimated 90% Medical Care Act regarding clinical pharmaceutical of all stored samples). In these biobanks, there are trials. sample collections stored from the early 1900s, but Sweden has a uniform healthcare system consisting it was not until the mid-1960s that samples began of 21 county councils/regions, where of 7 have to be collected to a greater extent. In addition to university hospitals (university county councils/ biobanks at county councils/regions and universities, regions).Through agreements, there are established there are biobanks at private healthcare providers, collaborations between the 7 university hospitals and private laboratories, medical and medical technology the 7 academic universities with a medical faculty. In

6 the healthcare sector, a well-established infrastructure Register of biobanks for the handling of samples and information, as well The Health and Social Care Inspectorate (IVO) is as biobanking for care, has long been established. the authority that supervises the Swedish Biobanks When the same infrastructure is used for research, in Medical Care Act and manages a register of all it is cost-effective, patient safe, quality assured, and biobanks in Sweden. Principals (the legal entity in accordance with the regulations covering the responsible for a biobank) who decide to establish healthcare sector, provides increased accessibility a biobank must notify the decision to IVO. When across the country. Therefore, universities and the biobanks are registered at IVO, they are assigned healthcare sector collaborate on biobanking of a unique number that is important for traceability research samples, which means that samples for and should be stated in biobank applications for research often, but not always, are stored in the access to samples. The registry does not contain data county councils/regions biobanks with a university on individual samples, but contains administrative hospital. The latter also applies to the 14 county information about the biobank, such as who the councils/regions that do not have a university principal is, who the biobank custodian is (person hospital. Sweden’s 21 county councils/regions are responsible for the biobank) as well as the purpose divided into six healthcare regions within which of the biobank. there is extended collaboration and joint functions, such as the Regional Biobank Centre (RBC Swedish “Regionalt biobankscentrum”).

7 3. Existing sample collections in Swedish biobanks

Samples collected for healthcare medical record. The content of LIS may differ depending on the type of IT system and the clinical purposes discipline. A LIS for clinical pathology/cytology can The largest sample collections consist of samples contain data regarding: donor’s identity linked to the collected in the healthcare sector for care, diagnostics internal ID number of the laboratory, data regarding and treatment (approximately 95 % of all stored consent linked to samples, date of sampling, when samples). They are stored in the county councils/ samples arrived at the laboratory, at what clinic regions biobanks or in the biobank of a supplier of samples were taken and what clinic the results should laboratory services with which the county council/ be sent to, type and quantity of sample material, region has an agreement. The largest sample what examinations and analyses as well as routine-, collections for healthcare purposes are within clinical special and immunostainings have been made, pathology and cytology (approximately 90 %), who has sought samples in the IT system, who has followed by clinical microbiology, the PKU biobank handled samples and what they did, diagnosis as well (approximately 5 % in total) and clinical genetics, as entity responsible for diagnosis. immunology, and chemistry. Materials primarily The county councils/regions are in the process stored are tissue (blocks and sections), cells/smear of establishing a joint register for traceability of cells, blood/plasma/serum and cerebrospinal stored samples, called the Swedish Biobank Registry fluid (CSF). These are materials used for analysis/ (SBR). The purpose of the SBR is to find samples diagnostics in laboratories for healthcare purposes. for the purposes of: changed consent, patient care, These samples can be used for follow-up of an and research and clinical trials. The SBR is under individual’s diagnosis and course of disease, quality construction and estimated to be available for use assurance, development work and education. They from 2020. are also important in the investigation of genetic diseases. Stored samples are also valuable in research Samples collected for research and clinical trials. In order to gain access to samples in any of these purposes sample collections, an approved biobank application, In Sweden, there are several large sample collections approved ethical vetting and consent from the and cohorts that specific researchers or research donor in accordance of the approval from an Ethics groups have completely or partially collected. These Review Board are required. See heading 7. “Biobank sample collections can be based on geographical application”. areas, specific age groups and/or diseases or For information on healthcare samples, conditions. In some of the sample collections, contact the biobank coordinator (Swedish persons or patients are monitored over time, which “Biobankssamordnare”) in your county council/ is of great value since it enables detection of risk region (contact information can be found at www. factors or disease markers. The research sample biobanksverige.se). collections mainly consist of blood/plasma or serum, but may also include RNA/DNA, urine, What information is registered about healthcare saliva or tissue. Consent from patient/donor is samples? collected during sampling, and approval from an Ethics Review Board is also required for the samples Information about samples collected for healthcare to be used for research. purposes is stored in the Laboratory Information Samples may also be available for research groups System (LIS) of the county council/region in and companies that have not been part of the question. The LIS information is a part of a patient’s collection of the samples. In order to gain access

8 to samples that are part of research collections, existing cohorts (contact information can be found approved ethical vetting and obtained consent is at www.biobanksverige.se) required in addition to the biobank application, and the applicant also has to obtain permission from the What information is registered about samples group or committee granting access to the respective collected for research? samples. See heading 7. “Biobank application”. The Information on samples collected for research Ethics Review Board will also decide if new consent purposes initiated from a research institution or a from the research participant is required before an healthcare provider can be stored in the laboratory existing sample can be used in the specified research information management system (LIMS). LIMS exist project. Using existing samples for research has at almost every university hospital/university and in practical advantages. It may shorten the start-up time some healthcare regions. Data registered in LIMS of the research project and the samples have already regards handling of samples from sampling until been characterized and quality controlled. storage. There is usually no data on analysis results or Information about existing cohorts can be found diagnostics, as such data is stored in another system at www.biobanksverige.se. Biobank coordinators by the researcher. (Swedish “Biobankssamordnare”) or biobanks with operative services can also provide guidance on

9 4. Collecting new samples In healthcare clinics, samples are taken and managed in the routine healthcare. Regardless of what purpose daily within the framework (often with requirements samples are collected for, they automatically receive of standardisation) of a specific research project or traceability of the handling, as well as information clinical trial according to the instructions of each regarding how and when the sample has been individual project/trial. This is particularly important handled. In other words, the routine, called healthcare in international studies where samples need to integrated biobanking for research (SIB) means that the be collected in the same way regardless of which collection and handling of research samples use country the sample is taken in. For more information existing structures in the routine healthcare. on advisory functions and support in planning The routine means that sampling can be ordered clinical studies, see www.kliniskastudier.se. in the electronic referral at the examining clinics, which allows sampling to be made by qualified Collecting new samples with known personnel on site when a patient is in for care. Each step is automatically recorded and the time from and high quality sampling to freezing is 0–4 hours. The samples are A routine for the collection and handling of liquid- frozen in smaller aliquots; thereby the whole sample based research samples has been implemented in the does not have to be thawed when analyses are to infrastructure of the routine healthcare for collecting take place. This ensures the quality of the remaining and handling samples at a number of hospitals in materials. Sampling and biobanking are done in Sweden. This existing high-quality and long-term accordance with the Swedish Biobanks in Medical infrastructure with competent staff around the clock, Care Act and the Ethical Review Act, and with the standardisation, traceability and documentation patient’s or donor’s consent. For more information ensures that samples collected for research purposes about what hospitals have implemented SIB, see maintain the same high quality as samples collected www.biobanksverige.se.

10 5. National registers and quality registers Because Sweden has population-based registers with the National Board of Health and Welfare (SoS). personal data, there are many reliable data sources There are also registers of interest for research for register research in Sweden. Sweden’s system e.g. at the Swedish Public Employment Service of unique personal identity numbers (Swedish: (Arbetsförmedlingen), the Swedish National Council “personnummer”) gives the opportunity to link for Crime Prevention (Brottsförebyggande rådet), the data about individuals from different data sources. Swedish Social Insurance Agency (Försäkringskassan) Registries of interest for research can be divided and the Swedish Defence Recruitment Agency into public governing registers, quality registers in (Rekryteringsmyndigheten). healthcare, biobanks and research generated data. The register authorities need to be contacted to get register data for research. Some register Information about registers in Sweden authorities have a dedicated point of contact for data requests, whereas others have none. The register Registerforskning.se service of the National Board of Health and Welfare The Swedish Research Council has compiled provides support for researchers who wish to order information about different registers, current statistics or individual data for research purposes. legislation, and how data for research is requested. The micro data unit of SCB helps researchers who The information is aimed at researchers who want want to order micro data. to use data from registers in their studies. For more If a researcher needs data from several authorities, information, see www.registerforskning.se. Statistics Sweden (SCB) can provide registers for certain other authorities, which can interact regarding Register Utiliser Tool (RUT) release of samples. The rules of the Public Access to Information and The Register Utiliser Tool (RUT) has been developed to Security Act determine whether register data can show register information on a meta-level to simplify be released. Each authority takes an independent register research. The work is in accordance with decision to release data for which they are the Swedish Research Council’s mission from the responsible. government and has been done in close cooperation with Swedish authorities holding registries. The purpose of RUT is to facilitate the Registers in universities identification and evaluation of registers and their Research databases/cohorts variables and provide structured information about There are registers created within specific research variables with associated metadata in the registry projects, so-called research generated registers. linked to the tool. There are also large research databases, which can RUT is currently being expanded, with the goal be considered a kind of infrastructure. The purpose of getting every governing register, quality register, is to serve several research projects, sometimes biobank, and research database frequently used in even within different scientific disciplines. From register-based research linked to this tool. an international perspective, Swedish cohorts are very useful as outcome events can be obtained National governing registers from public registers, such as the Prescribed Drugs National governing registers of great interest for research Register, the In-Patient Register, the Swedish are population and socioeconomic registers, health Cancer Registry and the Cause of Death Register, data registers as well as population based surveys whereby a complete follow-up of all individuals can and studies based on interviews. Most of these be obtained. The same principles as for samples registers are available at Statistics Sweden (SCB) and collected for research purposes usually apply for access to these data. Information about some of

11 these registers is available at the Swedish National continuously develop and ensure the quality of Data Service (in Swedish, SND) (www.snd.se). healthcare. The registers are used for improvement Information about several larger cohorts is also work and follow-up of healthcare as well as for available at the Swedish Cohort Consortium (www. research. The quality registers contain personal data cohorts.se). regarding healthcare, such as diagnosis, treatment, and results of treatment. Registers in County Councils/Regions The registers differ in quantity and setup and therefore differ in suitability for research. Therefore, National Quality Registers it is recommended to contact the register manager Today, there are 108 National Quality Registers or other representative of the steering group of operating under the healthcare system with an the register as early as possible. To access data from authority in a county council/region as the personal a national quality register, it is required that the data controller (CPUA). These registers have been CPUA decides that data may be disclosed. For more established in specific areas to systematically and information, see www.kvalitetsregister.se.

12 6. Rules and regulations for biobanks Samples and associated data to be used in research trials. Among other things, the law entails; are covered by the Ethical Review Act (2003:460), • A biobank is established by a decision by a the General Data Protection Regulation, GDPR principal owner (a legal entity, e.g. a healthcare (2016/679), and the Swedish Biobank in Medical Care provider, a unit for research or diagnostics, a Act (2002:297) as well as related regulations. public research institution or a pharmaceutical A requirement for identifiable samples to be used or a medical technology company). The in research is an approval from a regional Swedish principal designates a biobank custodian (person Ethics Review Board in accordance with the Ethical responsible for the biobank) and reports the Review Act. The ethical vetting also involves a review decision to establish a biobank to IVO. IVO then of whether processing of personal data in the project assigns the biobank a unique number. takes place in accordance with the provisions of the • Every sample taken within a healthcare provider’s GDPR (Article 9). operations is included in the primary sample collection in the healthcare provider’s biobank. The Swedish “Biobank in Medical Care Act” This applies regardless of whether the collection The Swedish Biobank in Medical Care Act makes it takes place on behalf of another principal’s possible to use samples in healthcare and treatment, operations or if the samples will be discarded national or international research, and development directly after analysis. in a way that guarantees the patient’s or donor’s • Samples in a biobank must be coded and safely integrity. stored so that there is no risk of samples being accidentally destroyed or accessed by anyone What samples does “Biobanks in Medical Care unauthorised. Act” apply to? • A regional Swedish Ethics Review Board must approve research projects (if applicable, including It applies to all samples in Sweden, with the research participant information and consent following exceptions, form) in accordance with the Ethical Review Act. • Routine samples for medical care (activity operating under the provisions of the Health • The biobank custodian handles applications for and Medical Service Act or the Dental Care Act) access to samples for research. For a biobank stored for < 2 months after analysis. Please custodian to approve an application, certain note, this exception does not apply to samples conditions are set: an approval in accordance with taken within healthcare with the purpose of the Ethical Review Act and consent from the donors research or clinical trials. that the samples be used for the specific purpose. • Samples can be made available for research or • If the donor takes samples outside the healthcare clinical trials by remaining in the biobank and being sector. analyzed on site, by being sent for analysis or investigation, • Anonymized samples (samples that neither or by being released from the healthcare principal’s directly nor indirectly can be linked to the sample biobank to the principal in whose project the donor). research will be conducted. • Samples that are a result or a product. • The Biobank in Medical Care Act also applies to samples sent for analysis abroad. If samples are to • Samples taken outside the borders of Sweden. be sent for analysis abroad, the biobank custodian of the biobank sending the samples, together with What does “Biobank in Medical Care Act” entail? the recipient abroad, must establish the terms that The Swedish Biobank in Medical Care Act regulates the samples are to be returned or destroyed when how samples taken within a healthcare provider’s they are no longer needed for the purpose for operations may be used in research and in clinical which they were sent.

13 • Sample collections released from healthcare the samples may only be used for research if the (secondary sample collection) may not be released donor changes the statement and agrees to the again. However, such samples may be sent for a project. specific measure, such as investigation or analysis. • If samples for research purposes are to be sent • Samples that are being sent should normally be for analysis abroad, the donor must be informed coded. If a donor’s personal data is to be sent and consent to this. If coded samples are to be at the same time as a coded sample from the sent to a country within the EU/EEA (or other donor, they must be sent in such a way that the countries with adequate protection, see www. personal data cannot be linked to the sample datainspektionen.se), it may be enough to provide (pseudonymized). information that samples may be sent abroad for • Samples from a biobank may not be released or transferred for profit. • Transfer of a biobank, or parts of a biobank, or closure of a biobank must be approved by the IVO.

Information and consent Provisions regarding consent from the donor and providing information to the donor (or person who can consent on the donor’s behalf) in the Swedish Biobanks in Medical Care Act state that; •• The donor (or person who will decide on the donor’s behalf) must be informed that a sample may be saved and for what purpose, and consent to this. • Consent must be documented in the patient’s medical record. • The donor has the right to withdraw consent at any time. This also applies to samples taken and stored before the Swedish Biobanks in Medical Care Act came into force. If the withdrawal applies to all types of use, the samples shall be destroyed or anonymized immediately (i.e., as soon as possible). This requires that each individual sample, that the Biobank Act applies to, can be traced and found.

• Samples may not be used for purposes other than analysis. However, if samples are to be sent to those covered by prior information and consent third countries, it is required that the information without the donor being informed and consenting clearly states that samples may be sent for analysis to the new purpose. But an Ethics Review Board to countries outside the EU/EEA. may grant exceptions to this rule. If samples are to be used for a new purpose related to • In research cases, the principal investigator for research or clinical trials, the information and the project must ensure that the information and consent regarding the new purpose must meet consent requirements are met, unless another the requirements established in the prior research agreement is made with the biobank where the ethics trial. If a donor has previously submitted samples are stored. a withdrawal of consent stating that samples may not be used for the purpose of research, More information about the Swedish Biobanks

14 in Medical Care Act and research participant to be responsible for the samples. This means information can be found at www.biobanksverige.se the healthcare principal will be given continued and www.epn.se. responsibility for the samples during the research project, including traceability of samples when Biobank responsibility of samples in studies consent is changed. Thus, county councils/regions establish a Material Transfer Agreement (MTA) All samples covered by the Swedish Biobanks in with the receiving laboratory that regulates how the Medical Care Act must be established in a sample samples will be handled during and after the study collection in a biobank with a biobank custodian who (see 6. Biobank application). has been appointed by the principal of the biobank. Universities and county councils/regions have Proposal of a new Swedish “Biobanks in Medical Care Act” On behalf of the government, an investigator has made a proposal for more expedient regulation of biobanks in Sweden. Among other things, the directive of the investigation included reviewing how the use of biological materials in biobanks, in combination with various registry data such as population-based registers, can be made available with the aim of internationally strengthening Sweden’s competitiveness in high quality medical research while maintaining protection of personal integrity. The proposal was submitted in January 2018. A new Swedish Biobanks in Medical Care Act can come into force in 2019 at the earliest.

Other legislations Processing of personal data The Swedish Biobanks in Medical Care Act regulates how samples may be used, whereas usage and release of personal data is regulated by the Public Access to Information and Secrecy Act (OSL) as well as regulations in the Personal Data Act and the Patient Data Act. The Regulation (EU) 2016/679 of the European Parliament and of the Council of 27 April 2016 on the protection of natural persons with regard to the processing of personal data and the free movement of such data, agreements resulting in universities often storing and repealing Directive 95/46/EC (General Data their sample collection in the county councils/ Protection Regulation/GDPR) entered into force regions biobanks. The healthcare principal biobank on May 25, 2018. The GDPR aims to strengthen custodians therefore have formal responsibility for individuals’ rights by regulating protection of the the sample collections. In sponsor-initiated studies, fundamental rights and freedoms of physical persons it is more common for samples to be released from with regards to the processing of personal data, as the healthcare principal’s biobank to the company’s well as to harmonize data privacy laws across the biobank in Sweden or to a biobank in Sweden with EU to enable the free movement of personal data which the company has an agreement. In cases within the EU. The law provides detailed rules on where the company does not have a biobank in processing personal data. The GDPR regulates Sweden, the principal, by agreement, may continue processing of personal data in a personal data

15 controller’s operation, unless special rules exist in an exception from the consent rule has been given by the Patient Data Act (2008:355). The Patient Data Act an Ethics Review Board for another reason, access regulates automated processing of personal data to a medical record may be given after assessment of (patient records) in the healthcare sector. Personal harm from the healthcare provider. An assessment data processed in a research study is governed by the of harm means that the person responsible for provisions in the GDPR. release of data from a patient’s medical record assesses whether or not the release is of harm for the Samples and personal data in research patient or the patient’s genetic relatives. Research concerning sensitive personal data, which It is stated in the Public Access to Information and Secrecy involves a physical intervention on a research Act (2009:400) who is responsible for the assessment participant or relates to biological material that has of harm. The Act states that if an employee of an been taken from a living or deceased person and authority, in accordance with the procedure or due can be traced to that person, in accordance with the to specific decisions, is responsible for the care of a Act concerning the Ethical Review of Research Involving record (such as a medical record), it is primarily that Humans (2003:460) (Ethical Review Act), may only be person who determines if the record can be disclosed. conducted if approved by an Ethics Review Board. In case of doubt, the employee must let the authority The purpose of the Ethical Review Act is to protect investigate if it can be done without unnecessary individuals and human integrity when research is delay. Within healthcare, it is primarily the person conducted. The ethical vetting also involves a review responsible for the patient’s medical record who is of whether processing of personal data in the project responsible for assessing the risk of harm. This is is in accordance with the provisions of article 9 in the usually the head of operations at the healthcare unit/ GDPR. Article 9 of the GDPR means that specific clinic where the information is available. categories of personal data (sensitive personal data), such as genetic or biometric data or health data, Regarding clinical trials of pharmaceutical drugs may be used for research purposes only if a special and medical technological products protective measure is taken, e.g. ethical vetting. In clinical trials (clinical pharmaceutical trials or How may clinical data be released? clinical trials of medical technological products when the product is to be tested on humans), Release of clinical data from a biobank, i.e., data an approval from the Swedish Medical Products from a patient’s medical record (such as information Agency is required. For more information, see about examinations results from analyses or www.lakemedelsverket.se. diagnosis), require approval from an Ethics Review Board as well as consent from the patient. If the New EU Regulation on clinical pharmaceutical patient’s consent cannot be obtained, e.g., if the trials – came into effect on 16 April 2014 (expected patient is deceased, decision-making incapable or if to be implemented in the autumn 2019) On 16 April 2014 the Regulation (EU) No 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use and repealing Directive 2001/20/ EC (EU regulation on clinical pharmaceutical trials) was adopted. The purpose of the EU regulation is to simplify the authorisation procedure within the EU and make the application process faster. In Sweden, the government has assigned the Swedish Medical Products Agency and the Regional Ethics Review Boards the task to create structures and forms of cooperation to ensure that decisions on access can be made in accordance with the regulation. To ensure that the process of cooperation is well-functioning when the regulation is to be applied, a joint pilot project has been initiated, which means that

16 applications included in the pilot project are handled technological and in vitro diagnostics (IVD) nationally in a process that replaces the regular products. Two new EU regulations have been handling of the Swedish Medical Products Agency, adopted to gradually replace the current three the Ethical Review Boards and the Regional Biobank directives. The purpose of the regulations is Centres (RBC). to establish a powerful, open, predictable and sustainable rule and regulation for medical New EU Regulation on medical technological technological and IVD products that guarantees products – went into effect on 26 May 2017 (with a high level of health and safety and supports gradual implementation) innovation. For more information, see www. There is also new legislation for medical lakemedelsverket.se. 7. Biobank applications To facilitate the management of requirements Release of samples: Upon release of samples, of the Swedish Biobanks in Medical Care Act, the responsibility and right to use them is transferred Sweden’s biobanks have, through Biobank Sweden, from the healthcare principal to the research joint principles and application forms for access principal or company. In accordance with the to biobank samples for research and clinical trials, Swedish Biobanks in Medical Care Act, IVO must as well as functions for be notified of any release of regulatory service in samples. Released samples formatting and signing of Upon release of samples, are referred to as secondary biobank agreements (see sample collections. Secondary heading 10. Advice and the responsi­bility and sample collection samples may practical support). Principles not be released further but and application forms are right to use them is transferred can be sent on for analysis. administered, updated and from the healthcare principal Release of samples requires established by working that the recipient has a biobank committee 1 on behalf to the research principal...” registered at IVO. More of Biobank Sweden (for information can be found at regulatory biobank service) www.ivo.se. and can be found at www.biobanksverige.se. See Send for analysis: For certain purposes, samples heading 12. Agreements and instructions. may be sent for analysis, from both primary and Research can be conducted both” on newly collected secondary sample collections to a recipient in Sweden samples for a specific study (according to study or abroad without it being considered a release of protocol or SIB) and on existing samples either taken samples. The samples are sent to the recipient for a in a healthcare context and stored for diagnostics, specific purpose, and are not placed at the disposal care and treatment or taken for research purposes). of the recipient. For newly collected samples, sampling can start as soon as the biobank application has been approved. What is required in order to use newly collected Samples can be made available either by releasing or existing samples in research? the samples to the research principal’s biobank in Sweden or by letting the samples remain in the • Decision of a biobank custodian (authorized healthcare principal’s biobank. Access to samples is representative of the principal’s biobank) based regulated in the biobank agreement. Irrespective of on a submitted biobank application together if samples remain in the principal’s biobank or are with applicable appendices. released to the research principal’s biobank, samples • An approved ethical vetting application in can be sent for analysis to a recipient biobank in accordance with the Ethical Review Act. The Sweden or abroad. approved ethical vetting application, the decision

17 and any completions to the biobank application Instructions for completion of biobank applications should also be submitted. This makes it possible can be found in document “K4. Instruction for for the biobank custodian to review whether the completion of form L1” and “M3. Instruction to application corresponds with the approval from MC N1a”. Documents can be found at www. the ethical vetting. If the biobank application biobanksverige.se. concerns existing samples, an assessment will also be made regarding availability of sufficient Where can I learn more? material to grant access (for further information, see paragraph “Special assessment for access to E-learning regarding the Swedish Biobanks in existing samples”). Medical Care Act: the Swedish Academy of Pharmaceutical Sciences, the National Biobank • Normally, explicit consent of the patient or donor Council (now Biobank Sweden), ASCRO and is needed, but the Ethics Review Board can grant LIF have developed a basic training course in the exceptions to the established requirements for Biobanks in Medical Care Act and handling of consent. If consent is required, it is important samples in clinical trials. For more information, see to append the research participant information www.lakemedelsakademin.se. approved by the Ethics Review Board, as well as the consent form. Please note, guidance on biobank agreements can Types of biobank applications for access to samples. be given by the county councils’/regions’ biobank 1. Biobank application in accordance with the coordinators or RBC before the decision by the multicentre principle: use in multicentre studies regional Ethics Review Board (see heading 10. with newly collected samples for the specific study to Advice and practical support). However, the formal be released to the receiving biobank in Sweden. In decision by the biobank custodian (or authorized these cases, one application (form N1a-N1b) can representative of the biobank) is taken when the be submitted to the Regional Biobank Centrum ethical application is approved. (RBC) located in the healthcare region where the ethical vetting was conducted. Setup of sample Which application form should I use? collections are established in the participating county councils’/regions’ e-biobanks and are Guidance regarding what application form to use can released through the biobank application where be found in Biobank Sweden’s document “K2. Form the RBC director, by proxy of the county selector”. An interactive form selector can be found at council’s/region’s e-biobank custodian, establishes www.biobanksverige.se. See heading 12. “Agreements a sample collection for the specific study. and instructions”. 2. Biobank application regarding single centre Guidance on how researchers and companies studies, newly collected samples not to be released or should act, what documents to use and what applications regarding existing samples (form appendices should be provided can be found in L1a with applicable appendices). The biobank document “C2c. Checklist for researchers” and “C2d. custodian (authorized representative of the Checklist – start research project based on biobank samples”. biobank) where samples will be established or are Documents can be found at www.biobanksverige.se stored will approve such an application.

18 Agreement if samples are to be sent for analysis conducted when the application arrives at an RBC or reaches the county council/regions biobank In cases where responsibility for samples will remain coordinator (or the biobank in question). The in the healthcare principal’s biobank and the samples administrative examination assures that: will be sent for analysis for research purposes, a Material Transfer Agreement (MTA) must be signed 1) the biobank application is complete and includes by the receiving biobank/laboratory before the all relevant appendices, as well as it being the most samples are sent. Among other things, the MTA current version, regulates how the receiving laboratory is allowed to 2) information about samples in the application for handle samples, especially in cases when they are no ethical vetting is the same as the study participants longer needed for the purpose for which they were have been informed of, sent. To simplify the process, the county councils/ 3) information about samples in the application regions use a joint form for MTA (form L2a) in cases for ethical vetting and the study participant where county councils/regions are responsible for information corresponds with the biobank samples sent abroad for research or clinical trials. The application. MTA form can be found at www.biobanksverige.se, form L2a (abroad) and L2b (within Sweden). Special assessment for access to existing healthcare samples A special assessment is made for biobank applications for access to existing samples (taken MTA form can in a healthcare context and stored for diagnostics, be found at care and treatment, or taken and stored for research purposes). www.biobanksverige.se...” When applying for existing healthcare samples, in addition to an administrative review, an assessment by the biobank custodian (alternatively, medically responsible individual/expert on their behalf) is made at the biobank regarding the requested How does the application process work? material, assuring When the biobank application has arrived at a RBC 1) that a reasonable amount is requested in relation or a county council’s/region’s biobank coordinator to the demand, (or the biobank in question), the application is ” 2) that the material is expected to meet the processed as described below. researcher’s needs. Processing of the biobank agreement at the An expert’s assessment that the request is reasonable biobank is particularly important since samples are a finite resource for individuals, healthcare and research. Regardless of whether the samples are newly collected This assessment requires the approved application or existing, an administrative examination of the for ethical vetting as well as applicable biobank biobank application and applicable appendices is

19 appendices (form L1a, L1b or L1c). Estimated time for handling and decision of a After a biobank application has been reviewed, the biobank application biobank custodian makes a decision. The samples The handling time depends on how complete the are then collected from the potential research application is when submitted, the need for advice participants/patients at the biobank. As the biobank and revisions, and the number of other applications application applies to existing samples, an approval simultaneously processed by the RBC, biobank of the biobank application does not guarantee access coordinator or biobank. Applications are handled in to all desired tissue material. This is due to the fact the order in which they reach the biobank. that the sample material must be sufficient for the The RBC or the county council’s/region’s biobank patient’s presumed care and may not run out, except coordinator can provide information about estimated in cases where there are strong reasons to believe this handling time. course of action will benefit the patient. In cases where a fast inclusion of a patient in an • In each case, it is confirmed that the donor has ongoing clinical trial is needed, there is a routine given consent to samples being used for research set by the county council’s/region’s biobank and that sufficient material is left for the patient’s coordinators (BBS) so the application is prioritized, diagnostics, care and treatment. and the inclusion and the biobank application are • It is also ensured that the quality of the remaining handled in parallel. The routine requires that an sample material does not deteriorate if access is approved application for ethical vetting exists and giving to the sample material. that an approved biobank application is granted by the county council/region where the study is • In exceptional cases, if there is limited material, conducted. For more information, contact the scientific expertise may need to be consulted to biobank coordinator in the county council/region ensure the possibility of future research involving where the study was approved. Contact information the same material. can be found at www.biobanksverige.se. Please note, there may also exist samples available for research in existing sample collections/cohorts for research (see below). Quantity, time and degree of access The quantity of samples that are made accessible Special assessment for access to existing and the amount of time samples may be used in the research samples (in existing sample collections/ research project are factors directed by the approval cohorts for research) of the Swedish Ethics Review Board, consent from the donor and the agreement (biobank application) When applying for existing research samples, in addition with the biobank where the samples are stored. These to an administrative review of the biobank, an documents regulate quantity, time (duration of the assessment by the sample collection controller specified project), and degree of access (access during (alternatively by a steering group linked to the sample the study period or also after completion). Please note, collection controller, or scientific experts appointed for extended access to samples, consent to save the by the research principal) is made to ensure the sample after completion of the study must exist. scientific question is sufficiently important for the material to be used. In addition, it is assessed if a reasonable amount is requested in relation to the Compensation and charges demand and if the material is expected to meet the • In accordance with the Swedish Biobanks in researcher’s needs. Instructions for how to apply Medical Care Act, samples or parts of samples for access are given by respective research sample stored in a biobank may not be released or collection. Samples collected for research purposes transferred for profit. On the other hand, the have been collected with the patient’s consent and biobank or the research sample collection it is important that the biobank assesses that the controller may have a charge to cover its costs. consent covers the new inquiry. A requirement for • There are several charges to take into account access is an approved application for ethical vetting when accessing samples (newly collected or for the research to be conducted, as well as applicable existing), e.g. costs for sampling, handling of biobank appendices (form L1a, L1b or L1c). samples, starting fee (on setup of healthcare

20 integrated biobanking, SIB), storage and retrieval keep the following in mind; of samples, as well as taking out and preparing • A trial by an Ethics Review Board is required. In existing samples, and administrative charges such many cases, this means that an advisory statement as establishing agreements, sending samples and is given if the Ethics Review Boards define that the records. Contact the biobank coordinator or the material is not to be used for research. An approval biobank for more information about costs. or advisory statement is required for the operations to be able to address the issue and feel confident Access to anonymized material for that the law is being followed. quality certification • Consent from the donor is required when collecting specific newly collected samples. Anonymized samples required for quality certification may come from many types of • For existing samples, the donor must not have sources, e.g. existing tissue samples from clinical restricted consent. pathology, existing liquid-based samples from • Use the biobank application form (L1 with clinical microbiology, tissue samples from transplant applicable appendices) for access to existing donors or specific samples collected for the quality samples or for collecting new samples. certification. There is legal basis for accessing all types of sources, but in practice it is not easy to • In cases of new collection of specific samples, know what is required in a specific case. a more comprehensive service may be required. Researchers/companies wanting access to Contact the county council’s/region’s biobank anonymized material for quality certification should coordinator for more information (www. biobanksverige.se). 8. Ownership and publication

Ownership of samples addition, when using research sample collections, it often means that the researchers responsible for the In legal terms, it is not meaningful to talk about sample collection have participated in the design of ownership of samples in Swedish biobanks. The the study and data retrieval to the extent that they foundational principle is that of joint opportunity to should be offered co-authorship when publishing utilize Swedish biobanks. Swedish biobanks should results. be considered an important common health resource. Today, feedback from research studies or clinical trials There are biobank custodians with obligations in is very unusual, and better feedback would add value to accordance with current laws. These laws also allow the biobanks. In addition, authorities that grant funding rights, such as for the sample donors to give their for infrastructure development for research, require consent after receiving relevant information about that biobank operations that have received funds are the sampling. mentioned in the acknowledgement. The biobank service and infrastructure available Publishing and reporting of results for research is a joint cooperative measure and In order to maintain and further develop the Swedish resource. Researchers and companies using biobank biobank resources, it is valuable that researchers samples are expected to contribute to increasing the using samples and data from biobanks and registers value of biobanks. make their results available. When releasing samples, biobanks or research sample collections often have the requirement to be mentioned in the acknowledgement upon publication in scientific articles. The purpose is to identify published research results where biobank samples have been used. In

21 9. What can I do to facilitate the application process? • Prepare well ahead of time. will be responsible for the submitted research • Read the information about access to samples samples. as well as the information provided in this guide • Material is a finite and shared resource. Plan the (also found at www.biobanksverige.se). amount of material carefully and do not ask for • Use existing instructions and checklists – more material than needed for the study. complete biobank applications result in shorter • In order to enhance your and/or your turnaround time (available at www.biobanksverige.se). organisation’s knowledge of using biobank • Contact the biobank coordinator or RBC for samples in research, take advantage of available advice and guidance as early as possible. resources such as biobank training (e-learning) at the Swedish Academy of Pharmaceutical • If samples are to be sent for analysis abroad, Sciences. Courses are frequently organized within append a signed MTA (form L2a) together with county councils/regions, healthcare regions and the biobank application if a county council/region universities (advertised on www.biobanksverige.se) 10. Advice and practical support Biobank Sweden has service and expanded support Practical sample handling and collecting new samples regarding access to samples for research or Every county council/region with a university with clinical trials. Contact information can be found at a medical faculty have introduced functions for www.biobanksverige.se. guidance and practical support regarding sample collection, handling of samples, access to samples, Regulatory biobank questions and biobank agreements etc. Guidance at university hospitals and universities Each county council/region has introduced is provided by the operative biobank service. If functions for guidance and examinations of biobank needed, contact; agreements with the aim of streamlining the process • Within each county council/region: the county and completing the documents before they are sent council’s/region’s biobank coordinator (BBS). to the biobank for a decision. Several places also • Within each university county council/region offer advice on how to complete research participant and University: Biobank facilities for extended information documents and the biobank section operative biobank service. in applications for ethical vetting, as well as aid in • If it is unclear where questions designing and establishing biobank agreements. For advice on biobank applications/establishment Planning of studies including access to existing of biobank agreements, Material Transfer Agreements healthcare samples (MTA), biobank section in applications for ethical vetting If access to existing samples is needed, it is advisable and research participant information, please contact; to include (or consult with) representatives of the • Within each county council/region: the county clinical profession (e.g. pathologist), preferably in the council’s/region’s biobank coordinator (BBS). planning of the study, so the requests are reasonable • Within each healthcare region: Regional Biobank and can be expected to answer the question at issue. Centre (RBC). Particularly regarding agreements There are established procedures for access to under the multicentre principle (form N1a). existing healthcare samples in every county council/ • General questions regarding agreements and region. For more information, contact your county regulatory questions regarding the Swedish council’s/region’s biobank coordinator. Biobanks in Medical Care Act can also be sent to [email protected]

22 Contact information Email addresses and phone numbers can be found at www.biobanksverige.se.

11. Agreements and instructions Agreements and instructions can be found at Agreement when samples are to be sent for www.biobanksverige.se. analysis within Sweden – L2b. Agreement on samples sent for analysis Information about access to samples within Sweden (only available in Swedish) • C2c. Checklist for researchers Agreements when samples are to be sent for • C2d. Checklist – start a research project based on analysis abroad biobank samples – K5. Information about AGREEMENTS on • K1. Principles on access to samples for research the transfer of biological material (Material (only available in Swedish) Transfer Agreement, MTA) • K2. Form selector – L2a. MTA-AGREEMENT on the transfer of biological materials • K3. Example of information for research participants (only available in Swedish) Biobank agreement and instructions for – newly Biobank agreement and instructions for – single collected samples to be released centre studies, newly collected samples not to be released • M3. Instruction for completion of the multicentre or applications regarding existing samples. form • K4. Instruction for completion of L1: Access to • N1a. Access to newly collected biobank samples in sample collection multicentre studies • N1b. Appendix B – principal investigators included • L1. Access to sample collection and personal data in the study for research • N2. Supplement to multicentre study application • L1a. Appendix: Information about existing clinical • N3a. Report on completed sampling in multicentre samples in pathology and cytology biobanks studies • L1b. Appendix: Information about existing liquid- • N3b. Appendix 1: Report on completed sampling based samples in biobanks (only total number of individuals/site) • L1c. Appendix: Information about existing samples • N4. Signing of power of attorney in the PKU biobank (only available in Swedish)

23 12. Planning

Preparations Access to samples before contacting Biobank through release Idea Planning Publication RBC/BBS and application or to send for operative service analysis What type of sample/ See For advice on Requirements; Requirements; If terms and conditions material is needed for www.biobanksverige.se biobank questions • Approved application • Approved biobank exist in the approved the study? to find information, in an application for for ethical vetting. application, application for access instructions etc. ethical vetting, please • Information for completed using the to samples – remember Are newly collected contact the biobank research participants national biobanks to mention the biobank samples needed E-learning is coordinator (BBS)/RBC with forms for application forms or the research sample (see heading 4) or available via the (see heading 10). informed consent (see headings 7 and collection in the are there samples Swedish Academy For advice on the signed by patient/ 12). acknowledgement already collected for of Pharmaceutical biobank application, donor (unless the when publishing the the purpose of care or Sciences please contact the Ethics Review Please keep in mind; results. research (see heading biobank coordinator Board decides that • Samples must be 3). (BBS)/RBC (see heading collection of consent pseudonymised. 10). is not required). • If samples are sent For technical advice, • Biobank application, within Sweden please contact the including relevant for analysis from operative service (see appendices (see a biobank at a heading 10). headings 7 and 12). hospital, – establish Applications can be agreement L2b Please keep in mind; done either by the with the analysing The biobank multicentre principle laboratory. application can or be sent to each • If samples are sent be prepared biobank separately abroad for analysis simultaneously with (see heading 7). from a biobank at a the application for hospital – establish ethical vetting, but Please keep in mind; L2a with the a decision cannot Incomplete biobank analysing laboratory. be made until the applications will application for ethical prolong the time Please note, in cases vetting is approved. before a biobank where samples are custodian can make not released from the Tips; decisions. healthcare principal’s If newly collected biobank, append L2a/ samples with high Tips; L2b to the biobank quality are needed in RBC offers application if samples accordance with SIB administrative review are to be sent for (see heading 4), please of biobank agreements analysis. contact the operative for existing samples biobank service or the from several biobanks. If samples are released, biobank coordinator The purpose of the receiving biobank (BBS) (see heading 10) this is to facilitate is responsible for If existing samples are for applicants and making sure that L2a/ required, it is useful if a involved biobanks. See L2b or equivalent clinical representative www.biobanksverige.se. is established when is involved in the samples are sent. planning (e.g. pathologist).

WORKING GROUP FOR ELABORATION OF THIS GUIDE: Karolina Antonov (Läkemedelsindustriföreningen), Gunilla Bergström (RBC Sydöstra sjukvårdsregionen), Sonja Eaker (Beredningsgrupp Biobank Sverige), Malin Hollmark (Swedish Medtech), Östen Karlsson, (Läkemedelsindustriföreningen), Hasse Knutsson (Sveriges Kommuner och Landsting), Chatarina Larsson (Uppsala universitet), Pål Resare (Sveriges Kommuner och Landsting).

EDITORIAL: Jessica Seger (RBC Uppsala Örebro), Hemma Hvitfeldt (RBC Västra Götaland).

24 Appendix 1. Vocabulary Biobank: An organized unit responsible for one or more sample collections taken in healthcare and Secondary sample collection: Sample collection stored for more than two months after analysis released from the biobank responsible for the (the exception does not apply to samples taken for primary sample collection. Samples from a secondary research) and can be traced to a certain person. sample collection may not be released further but can be sent for analysis within Sweden or abroad. E-biobank: A registry at a healthcare provider containing information about samples taken for Anonymized: Measure causing the origin of a research studies that are released to a research sample to neither directly nor indirectly be traced to principal/equivalent directly after sampling. The the person or fetus a sample derives from. e-biobank serves as a virtual primary sample collection, i.e. it only contains administrative data Coding: Measure that replaces directly identifying about what study sample collections were collected data with a code so the origin of a sample can only for, and to what biobank samples were released. indirectly be traced to the donor from whom the There is no information about individual persons or sample derives. sample results. Pseudonymisation: Processing of personal data Sample: Biological material from a living or resulting in the data no longer being attributed deceased person or fetus, regardless of the chemical to a specific individual without using additional composition of the sample (organs, solid and liquid information, provided that the additional tissue, cells and cell lines, genes or parts of genes and information is kept separately and is subject to other forms of biological material). technical and organisational measures that ensure that personal data are not attributed to an identified Sample collection: Collection of samples with at or identifiable physical person. least one common characteristic. Biobanks generally contain one or more sample collections. Healthcare integrated biobanking (in Swedish, SIB): Healthcare integrated collection and handling Primary sample collection: Sample collection of liquid-based samples for research with an included in a biobank established in a healthcare aliquoting process implemented in the regular provider’s healthcare operations in Sweden. healthcare infrastructure.

25 Appendix 2. Roles and Services Sweden has a comprehensive national service and Operative biobank service for research: Available collaboration structure in the biobank sector. The in all county councils/regions, and includes support association Biobank Sweden is described on page 5. for planning of study, collection, handling, storage, The key features are described below. retrieval of samples and IT support for a sample collection. At university hospitals/universities, Principal of a biobank: Every biobank has a there is Extended operational biobank service, with principal. Only a legal entity can be principal of additional resources for researchers in planning and a biobank, e.g. healthcare provider, university, implementing a study involving biobank samples. pharmaceutical company. Sample collection controllers for research sample Biobank custodian: Every biobank has a collections/cohorts: All sample collections or custodian, who is designated by the principal, and cohorts saved for research purposes have a sample has operative responsibility for the biobank, making collection controller, or some sort of steering group, sure that the requirements of the Swedish Biobanks that decides on access to a sample collection/cohort in Medical Care Act are enforced. The biobank before a formal decision on access is made by the custodian is responsible for the existence of routines biobank custodian. for destruction or anonymisation of samples, testing applications for access to samples for Sample service coordinators: located at the research, deciding on the establishment of sample university hospitals/universities with extended collections and release of samples, and signing biobank service. They provide support in the biobank agreements with an applicant (responsible planning and start-up of research studies that will researcher/primary investigator) and, in applicable be collected on several sites in accordance with cases, receiving biobanks. However, in many places in healthcare integrated biobanking. Sweden, it is the biobank coordinator in the county council/region in question who administratively Regional Biobank Centre (RBC): There is an reviews the application for access to samples before a RBC in each healthcare region in Sweden (six in decision is made. total). RBC is a service- and centre of excellence that provides guidance and support to pharmaceutical Biobank coordinator (in Swedish, companies and the public regarding the Swedish Biobankssamordnare, BBS): Sweden’s county Biobanks in Medical Care Act. They work according to councils/regions have chosen to delegate the multicentre principle regarding access to newly responsibility of coordination of the principal’s/ collected samples that are going to be released. The principals’ biobanks to a biobank coordinator. RBC is also responsible for administering, updating Biobank coordinators offer researchers and and establishing Biobank Sweden’s joint documents companies advice on the Swedish Biobanks in Medical and website. Care Act, biobank applications and biobank services. It is primarily the biobank coordinator in the county Contact information can be found at www. council/region where a study is to be conducted that biobanksverige.se should be contacted for questions on biobanking, access to existing healthcare samples, and existence of research samples/cohorts or application forms. They can also provide advice regarding biobank questions on the application for ethical vetting and patient information before submission to the Ethics Review Board.

26 Appendix 3. Definitions of entities responsible for a project Different regulations result in different definitions. Researcher/investigator: Principal (legal entity) responsible for the project: • Clinical pharmaceutical trials/medical technological products • Clinical pharmaceutical trial/medical technological – Investigator: An individual responsible for products the conduct of a clinical trial/investigation at a – Sponsor: An individual, company, institution clinical trial site/investigation site.. or organisation that takes responsibility for the • Medical technological products initiation, management and setup of financing of a clinical trial. – Researcher locally responsible for conducting the project. • Ethical vetting – Entity principally responsible for research Research participant: (research principal): A government authority or a physical or legal entity under whose • Clinical pharmaceutical trials auspices the research is conducted. – Subject: An individual who participates – Please note, when applying for ethical in a clinical trial, either as recipient of an vetting, it must also be stated whether the investigational medicinal product or as a control research is commissioned and in such cases person. who the principal is, e.g. a company (clinical • Medical technological products pharmaceutical trial or trial of other new – Subject: An individual who participates in a products), an organisation or an authority. clinical investigation. Principal/primary investigator: • Ethical vetting – Research participant: A living person who is • Clinical pharmaceutical trials/medical the subject of the research. technological products – Principal investigator: An investigator who is the responsible leader for a team of investigators who conduct a clinical trial at a clinical trial site. If the clinical trial has REFERENCES: multiple trial sites/medical centres or clinics • Läkemedelsverket.se (multicentre), one investigator is appointed to • REGULATION (EU) No 536/2014 OF THE coordinate the work (coordinating investigator). EUROPEAN PARLIAMENT AND OF THE COUNCIL • Ethical vetting of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive – Researcher with primary responsibility 2001/20/EC (Text with EEA relevance) for the complementation of the project • REGULATION (EU) 2017/745 OF THE EUROPEAN (principal contact). Responsible for ensuring PARLIAMENT AND OF THE COUNCIL of 5 April that those locally implementing a project have 2017 on medical devices, amending Directive sufficient competence to conduct the project 2001/83/EC, Regulation (EC) No 178/2002 and and are familiar with “Good Clinical Practice” Regulation (EC) No 1223/2009 and repealing (GCP), in the interest of the research participants’ Council Directives 90/385/EEC and 93/42/EEC safety. If several responsible research bodies are • Lag (2003:460) om etikprövning av forskning involved, or if several researchers within the same som avser människor och Vägledning till responsible research body are cooperating on the ansökningsblankett (www.epn.se) same project, one researcher is appointed principal investigator, and is the contact person for the ethical vetting board.

27 Appendix 4. Research samples not covered by the Biobanks in Medical Care Act On 1 January 2019, a new exemption was introduced If samples are collected for a biobank or used for into Chapter 1, Section 3, Paragraph 4 of the any other purpose than that for which they were Biobanks in Medical Care Act (2002:297) regarding taken, the Biobanks Act will apply. samples taken for research but not to be stored in a biobank. This change is due to the adaptation Examples of samples covered by the exemption of Swedish legislation to the EU Clinical Trials rule Regulation. • Samples analysed directly (e.g., ward, clinic, healthcare centre) and that are destroyed 1. What does this exemption mean? immediately following analysis. • Routine tests in clinical chemistry, for example, This exemption means that the Biobanks Act does blood count, electrolytes, CRP, etc. analysed at not apply to samples intended for research that are a local laboratory and destroyed immediately analysed within six months of the sampling date following the analysis. and that are immediately destroyed following their analysis. Both conditions must be met. Biobank Sweden recommends that any researcher/ The exemption only applies to studies that have company unsure whether the samples in a study are received ethical approval after 1 January 2019. This covered by the exemption or not should contact the is because both ethical approval and consent must county council/regional biobank coordinator, or a correspond to the handling of samples. Regional Biobank Centre (RBC) for advice.

28 2. What is meant by “immediately 4. Is an MTA necessary if samples are following the analysis”? sent for analysis? Biobank Sweden defines immediately following the If a local authority/region is the research principal: analysis, as a maximum of 1–2 days after an analysis Yes. A Material Transfer Agreement (MTA) is has been carried out for the purpose for which always required if a sample will be sent for analysis, samples were taken, for example a patient’s blood regardless of whether it is covered by the Biobanks values allowing study medication to be administered. in Medical Care Act or not. That is to say, the time required to ensure that the If another principal is the research principal: analysis has been performed correctly and does not Biobank Sweden recommends that an MTA is always need to be re-done. established if samples will be sent for analysis, regardless of whether the sample is or is not covered 3. Is an application for ethical approval by the Biobanks in Medical Care Act. However, note needed? that it is not always the case that a separate MTA needs to be established. For example, a separate Yes. An application for ethical approval is required MTA is not necessary if the agreement between regardless of whether a sample is covered by the sponsor and central laboratory corresponds to the Biobanks in Medical Care Act or not. Research contents of the MTA. involving a physical intervention on a research subject or involving biological materials created from About MTA: a living or deceased person that can be traced to The Agreement (MTA) is used to regulate how an individual must only, in accordance with the Act samples may be handled by the recipient; how the concerning the Ethical Review of Research Involving Humans recipient may handle samples and sample code and (2003:460) (Ethical Review Act), be conducted where how samples and sample codes must be handled ethical approval has been granted. when they are no longer needed for the agreed This means that ethical approval is always required purposes. when biological samples will be used for or handled Note: Samples sent must be coded or pseudonymised. in research. If personal data will also be sent to the recipient, a data processing agreement must be established

29 between the personal data controller and recipient Care Act, but are described in the application for (see document K5). ethical approval and in the consent form such that handling is within the scope of the exemption. 5. Recommendation in case of doubt Should errors arise, there is a risk of the research study having to discard the samples, even if they are Should there be any doubt as to whether the sample still required for the study. falls under the exemption rule or not, Biobank This would mean that there is no valid ethical Sweden recommends that samples be handled as approval for retention, consent, and that samples though they were subject to the Biobanks in Medical are not stored in a biobank in accordance with the Care Act. This means describing their retention Biobanks in Medical Care Act. in the application for ethical approval and in the The Biobanks in Medical Care Act provides special information for research subjects and establishing a rights for sample donors and special protection for biobank agreement with the biobank custodian at the samples. This implies, for example, that the donor healthcare provider where samples will be collected. must be asked if samples may be stored in a biobank The same recommendation applies if samples and informed about the right to withdraw or limit are to be sent for analysis to a recipient outside of their consent previously given. There must always be their own principal and there are no procedures or a biobank custodian appointed by the principal. The templates to be able to establish an MTA. custodian has special responsibility to ensure that samples covered by the law are fully traceable. 6. What happens if there is an error, i.e. if The Swedish Ethical Review Authority will assess there is no ethical approval and biobank whether samples may be stored in a biobank for research purposes. Furthermore, only the Swedish agreement for retention of samples? Ethical Review Authority (or the Ethics Review The research study will always encounter problems Appeals Board) may authorise exemptions from the if it becomes clear at a later stage that samples in requirement for information and consent for samples a study are to be covered by the Biobanks in Medical to be retained in a biobank.

30 What can the applicant do if at a later stage, it turns out that samples in a study in fact falls under the Biobanks in Medical Care Act? For example: • if samples are destroyed within 6 months, but not immediately following the analysis, • if samples will be stored for more than six months, SUMMARY • if samples will be used for other analyses than •The exemption for research applies to samples analysed within six months of their date of collection and destroyed those described in the application for ethical immediately following the analysis. Both conditions must be approval met. • Biobank Sweden defines “immediately following the analysis” Within 6 months of sample collection as a maximum of 1-2 days after completion of the analysis, The project has two options: i.e., the time it takes to ensure that the analysis has been conducted correctly and does not need to be re-done. 1. A supplementary application is sent to the Ethical Review Authority. The Ethical Review Authority • The exemption only applies to studies that have received ethical approval after 1 January 2019. This is because both needs to be informed when the sample collection ethical approval and consent must correspond to handling has taken place. If the application is approved the samples. by the Ethical Review Authority, the sample • The exemption does not apply if the samples are collected for collection will be set up (registered) in a biobank a biobank or used for any other purpose than that for which at the healthcare provider where the samples were they were taken. taken and suitable agreements can be established • Ethical approval is always necessary. Physical sampling retrospectively, depending on whether samples and handling of samples is covered by the Ethical Review will be analysed on site, sent for analysis or Act, regardless of whether the samples are covered by the released. Biobanks in Medical Care Act or not. Note: The application needs to be sent to the • If a sample will be sent for analysis, a Material Transfer Ethical Review Authority in good time, as the Agreement (MTA) is always required, regardless of whether it decision must be made by the Authority before is covered by the Biobanks in Medical Care Act or not. the 6-month period from sample collection • Problems may arise for the research study if it becomes clear has passed. As a guideline, the supplementary at a later stage that samples in a study are to be covered by application should be sent to the Ethical Review the Biobanks in Medical Care Act, but are described in the Authority at least 2 months before the 6-month application for ethical approval and consent form such that period from date of sampling has passed. handling is within the scope of the exemption rule. In some cases, a supplementary application to the Ethical Review 2. Samples are discarded (destroyed or anonymised) Authority may be possible. Note that the Ethical Review immediately. Authority must have issued its decision on the supplementary application before the 6-month period from time of sampling After 6 months from sample collection has expired. The research principal has illegal sample handling • Treat samples as though they are subject to the Biobanks in Medical Care Act if there is any doubt as to whether the and samples must be discarded (destroyed or sample falls under the exemption rule or not. The same anonymised) immediately. applies if samples are to be sent for analysis to a recipient outside of their own principal and there are no routines or Read more templates to establish an MTA. More information about the changes and background can be found in the Government Bill Adaptations of Swedish law to the EU Clinical Trials Regulation, Govt Bill 2017/18:196. (https://www.regeringen. se/ rattsliga-dokument/proposition/2018/03/prop- 201718196/) (in Swedish)

31 19-1133. Form och layout: Byrå4, 2019. Byrå4, Form och layout: 19-1133.

Would you like to know more about the Biobanks In Medical Care Act? Would you like to know about existing biobanks? Or learn more about research ethics? The following websites are recommended if you are looking for further information: www.biobanksverige.se www.1177.se

Legislative documentation can be found at www.riksdagen.se

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